Strong evidence indicates that the long-recognized 30-40% of patients with type 1 diabetes mellitus (DM) who are at specific risk of nephropathy carry that risk because of two factors, glycemic control and genes. The genetic contributors appear to involve the hypertension process as they are associated with a strong family history of hypertension and increased red blood cell Na:Li countertransport. Several genes involving the renin-angiotensin system (RAS) have emerged as attractive candidates for detailed study, including polymorphism involving the angiotensinogen gene, ACE, and the AT1 receptor. A major barrier to successful genetic analysis of complex human traits is their multifactorial determination, specifically etiologic heterogeneity. Thus, the sole use of the distant phenotype as a dichotomous trait has limited progress. One powerful approach to increased etiologic homogeneity is to employ intermediate phenotypes, which are physiological or biochemical traits that identify specific subsets of patients for correlation with the gene of interest. The intermediate phenotype can also provide insight into the responsible physiological mechanisms. This study is designed to ascertain whether polymorphism in one or more of these genes in an epistatic relationship is associated with an alteration in angiotensin-mediated control of the renal circulation that predisposes to diabetic kidney disease, and to clarify the interaction between genes, glycemic control and expression of these physiologic abnormalities. Successful identification of intermediate phenotypes linked to specific genetic polymorphism would provide insight into current therapy, new approaches to identification of patients specifically at risk and improved preventative measures.